T cells responses against the EBV antigens have been elicited in Burkitt lymphoma (BL), nasopharyngeal cancer (NPC) and Hodgkin disease (HD), but have been insufficient to eradicate tumor cells. Current approach mainly focuses on CD8+T effector cells appears inadequate for the generation of optimal antitumor immunity. Increasing evidence from both human and animal studies indicates that CD4+ T (helper) cells play a central role in initiating and maintaining the host immune responses against cancer. While a few MHC class II-restricted EBNA1 peptides have been reported, the role of such peptides and their cognate CD4+ T cells in antitumor immunity is unknown. Thus, it is critical to develop a preclinical tumor model for developing novel strategies to enhance antitumor immune responses. We hypothesize that MHC class II-restricted peptides from EBNA1 as well as from previously unrecognized tumor antigens, can be identified in EBV-positive tumor cells and used to activate CD4+ T cells, leading to more potent antitumor immunity. To test this hypothesis, we propose to identify and evaluate MHC class II-restricted viral/tumor peptides from EVB-associated tumors. With these T helper epitopes in hand, their optimal use will require greater knowledge of effective vaccine strategies and the antitumor role of antigen-specific CD4+ T cells. A lack of an animal model for EBV-associated tumors poses a major obstacle for obtaining such knowledge and understanding of development of effective vaccines against EVB-associated cancer. Thus, we further propose to establish a murine BL model characterized by expression of EBNA1, and exploit it to define the role of CD4+ T cells in cellular immune responses against BL tumors by a novel antigen delivery system developed in the Pl's laboratory. Finally, we plan to elucidate the mechanism of CD4+ T-cell-mediated antitumor immunity, to determine whether CD4+ T cells exert antitumor effects by direct or indirect tumor killing mechanisms, and/or through the role of cytokines secreted by CD4+ T cells. It is anticipated that these studies will advance the field of immunotherapy of cancer and provide a foundation for the development of novel approaches for effective cancer vaccines.